There are many pathways and processes that appear to regulate the rate of aging and our susceptibility to age-related diseases such as neurodegeneration, atherosclerosis and cancer. One emerging process that has been increasingly implicated is the depletion, exhaustion or age-related dysfunction of adult stem cells. The mechanism behind why or how stem cells age has not been extensively studied. We have focused on the connection between intracellular metabolism and stem cell aging. Our hypothesis is that the control of metabolism and intracellular reactive oxygen species (ROS) within stem and progenitor cells is a key component of stem cell maintainence. Furthermore, we hypothesize that many of the genes implicated in stem cell regulation will also influnce the underlying metabolism of these cells. We have recently made an interesting connection between the Polycomb regulator Bmi1 and intracellular metabolism (Liu et al., Nature, 2009). Previous work has demonstrated that the absence of Bmi1 leads to a near total failure of stem cell self-renewal. Thus, Bmi1 activity and by extension Polycomb epigenetic regulation, is required to maintain both the hematopoietic an neural stem cell compartment. Our results also suggested that Bmi1 has important functions in regulating mitochondrial function as well as ROS homeostasis. In particular, in the absence of Bmi1, levels of ROS increase and are sufficient to activate the DNA damage response (DDR) pathways. We are currently pursuing the cellular targets of Bmi1, and in particular signaling pathways that this polycomb gene product might directly or indirectly regulate. We have also probed the connection between other regulators of stem cell biology and metabolism. One of our interests has been the connection between the Wnt signaling pathway and metabolism. Our recent data suggest that Wnt signaling plays an important role in mammalain metabolism particularly in the response of the liver to starvation (Liu et al, 2011). Current efforts are focused on the role of fatty acid oxidation (FAO)in stem cell function. In this regard, we have used genetic models to disrupt FAO to see how it might alter cell fate (see Nomura et al., Nat Imm, 2016). Other current efforts are to use additional genetic models to probe the relationship between mitochondrial function and stem cell function. We are also interested in mechanisms that regulate redox homeostasis in stem cells and somatic tissues. In addition, we have ongoing efforts to understand the role of metabolism in the cellular response to extracelluar ligands that regulate stem cell function.